During Labour's 13 years in opposition, from 1951 to 1964, Mayhew presented the Labour Party on television, both as a commentator on the BBC and as a presenter on Party Political Broadcasts. He introduced the first Labour broadcast, in 1951, in which he talked with Sir Hartley Shawcross. Mayhew also became known as one of the fiercest opponents of unilateral nuclear disarmament in the Labour Party. He also served as Shadow War Secretary from 1960 to 1961 and as a spokesman on foreign affairs from 1961 to 1964.

When Labour took office in 1964 Mayhew became Parliamentary Undersecretary of State for Defence, and was informally known as Minister for the Navy. However, in 1966, after the Wilson government decided to shift British airpower from carrier-based planes to land-based planes and cancel the CVA-01 aircraft carrier programme, Mayhew resigned along with the First Sea Lord, Sir David Luce.

In 1973 Mayhew offered £5,000 to anyone who could produce evidence that Nasser had stated that he sought to "drive the Jews into the sea". Mayhew repeated the offer later in the House of Commons (Hansard, 18 October 1973) and broadened it to include any genocidal statement by an Arab leader (The Guardian, 9 September 1974), while reserving for himself the right to be the arbiter of the authenticity of any purported statements as well as their meaning. Mayhew received several letters from claimants, each one producing one quotation or another from an Arab leader, all of which Mayhew deemed to be fabricated. One claimant, Warren Bergson, took Mayhew to court. The case came before the High Court in February 1976. Bergson was unable to offer evidence of Nasser's alleged statement and acknowledged that, after thorough research, he had been unable to find any statement by a responsible Arab leader that could be described as genocidal.

Mayhew had been feeling increasingly uneasy with Labour policies under Harold Wilson and in 1974 he defected to the Liberals, being the first Member of Parliament to cross the floor to the Liberals in several decades. In the general election in October 1974 Mayhew contested Bath instead of Woolwich East in order not to split his former constituency party. He was defeated in Bath, which he also unsuccessfully contested in 1979.

In 1955 Mayhew took part in an experiment that was intended to form a Panorama special for BBC TV, but was never broadcast. Under the guidance of his friend Dr Humphry Osmond Mayhew ingested 400 mg of mescaline hydrochloride and allowed himself to be filmed for the duration of the trip.[5] Samples of the audio were used in the psychedelic dance tracks "Mayhew Speaks Out" and "Christopher Mayhew Says" by British band The Shamen. Part of the footage was included in the BBC documentary LSD - The Beyond Within (1986).